MIDCAREER INVESTIGATOR AWARD IN PATIENT-ORIENTED RESEARCH (K24) This K24 application seeks support that is essential for the candidate's continued career development as an independent, patient-oriented researcher and mentor. The candidate has attained considerable expertise in the clinical neurobiology of stimulant addiction, employing convergent methodologies (neuroimaging, psychopharmacology, drug self-administration, and most recently, genetics). He has demonstrated considerable productivity as evidenced by peer-reviewed publications (both as principal and senior author) and extramural research support (6 R01s, 1 R03, 2 research training grants, 2 center grant sections, scientific co-directorship of a major center, and 6 foundation grant awards). However, expiration of the candidate's K02 has resulted in him having to assume major (>50%) clinical and administrative responsibilities unrelated to this research. This occurs at a critical time, as this new area (genetics) requires highly specialized training and increasing reliance of trainees on this expertise. Thus, the K24 award is vital for sustaining the candidate's patient-oriented research and research-related mentoring activates. Moreover, the award will enable the candidate's immersion in an area of rapid change, thereby facilitating his mastery of newly independent research skills in substance dependence genetics. Justification for the award is provided by a comprehensive 5-year career development plan which 1) allows the candidate to enhance skills in the genetics / pharmacogenetics of complex traits, and 2) enables the candidate to continue his mentoring of beginning investigators in clinical research. Intensive training is provided by an integrated curriculum of intramural coursework, extramural didactics, individualized preceptorships, interactive symposia, and research-related organizational meetings. Two representative research studies are presented in detail - including 1) a study of drug dependence in an isolated population (active) and 2) a pharmacogenetic study of cocaine, disulfiram and genetic variation (C-1021T) in the gene for dopamine beta-hydroxylase (DBH).